The complement system is an enzyme cascade by serine proteases that mainly assists in defense against infection. The complement system bridges innate immunity and adaptive immunity by amplifying antibody responses and immune memory, lysing foreign cells, removing immune complexes and apoptotic cells, and the like. Many complement components are proteins present as inert zymogens in the serum and play a role in a number of biological functions (chemotactic stimulation, induction of IgE-independent degranulation of mast cells, and the like). Three pathways, the classical pathway, lectin pathway, and alternative pathway, are known in complement activation.
In the classical pathway, the starting point of activation is the interaction of the complement component C1 protein and an antigen-IgM complex or antigen-IgG complex. The lectin pathway (mannose-binding lectin pathway) is activated independent of antibodies by bonding of mannose-binding lectin with mannose groups on the bacterial cell wall, following an activation pathway similar to that of the classical pathway. The alternative pathway is a pathway in which C3 (H2O) produced by adventitious hydrolysis is activated by factor B and factor D. It is spontaneously activated all the time, but is controlled by factor H, factor I, and other such control factors.
All three of the above pathways finally merge into a common pathway. This common pathway begins with C3 convertase cleaving C3 protein into C3a and C3b. The cleavage of C3 promotes the formation of membrane attack complexes that dissolve foreign cells, and the like.
The C1q molecule is the target recognition protein of the classical pathway. The C1q molecule is a heterocomplex constructed from chain A, chain B, and chain C and has a globular domain (gC1q domain) that recognizes the target. Each chain has a short N-terminal region followed by a collagen-like region (CLR), with a gC1q domain located on the C-terminal side of the collagen-like region (Non-patent Reference 1).
Many non-complement proteins having a similar structure to the gC1q domain (also referred to simply as “C1q domain” in this specification) of the C1q molecule are also known. There is a protein group called the C1QTNF superfamily based on the similarity of the tertiary structure of the gC1q domain to TNF. The CTRP (C1QTNF-related protein) family is part of this superfamily as a subfamily especially similar to complement C1q. Seventeen CTRP members have been found in humans.
CTRP1 is a protein discovered as a protein related to the G-protein-coupled receptor. It is expressed mainly in the heart and has a strong anti-troponin effect. CTRP6 and CTRP8 are homologs of CTRP1 and have similar domain structures, but differ in intron-exon pattern. CTRP2 and CTRP7 are thought to belong to the same subfamily based on sequence homology, similarity of domain structure, and intron-exon pattern. CTRP3 is known to promote the differentiation and growth of cartilage cells. CTRP4 alone among this group has one or more C1q domains. CTRP5 was discovered as a protein related to late-onset retinal degeneration and is expressed mainly in the retinal pigment epithelium, liver, lung, brain, and placenta (Patent Reference 1).
Since CTRP1 manifests a strong effect in the prevention of artery blockage and platelet activation, as was mentioned above, and its administration apparently does not induce any bleeding complications, it may be clinically useful in the treatment of various conditions associated with vascular damage, including coronary angioplasty, intimal resection of the carotid artery, and stroke (Patent Reference 2).
However, no relationship between CTRP6 and autoimmune disease due to complement activation is predicted in any of the prior art.